This invention relates to the field of vitamin D receptor agonists. The agonists can be used as drugs to treat a variety of diseases, including, but not limited to, bone disorders, cardiovascular disease, hyperparathyroidism, immune disorders, proliferative diseases, renal disease, and thrombosis.
Vitamin D3 is a precursor to the functionally active hormone, 1,25-dihydroxyvitamin D3. Vitamin D3 is made from 7-dehydrocholesterol in the skin after exposure to ultraviolet light, modified by vitamin D3-25-hydroxylase in the liver, and then by 25-hydroxyvitamin D3-1α-hydroxylase in the kidney to form the active hormone, 1,25-dihydroxyvitamin D3 (calcitriol, commercially available under the brand name CALCIJEX®). Calcitriol functions by binding to the Vitamin D receptor (VDR), a nuclear receptor. The binding of calcitriol to the VDR activates the receptor to recruit cofactors to form a complex that binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription.
Calcitriol plays a biochemical role in mineral homeostasis, which covers regulation of parathyroid hormone (PTH), intestinal calcium and phosphate absorption, and bone metabolism. Through the coordinated functions of PTH and calcitriol, the homeostasis of calcium and phosphorous is maintained.
VDR is widely distributed in organs and tissues throughout the body and is implicated in numerous disease states (e.g., cardiovascular diseases, immune disorders, oncology-related thrombosis, etc.).
Analogs of calcitriol have been developed, some having reduced hypercalcemic effect, and several analogs such as paricalcitol (ZEMPLAR®) and doxercalciferol (HECTOROL®) are currently on the market for the treatment of hyperparathyroidism secondary to chronic kidney disease. In addition, a few VDR modulators are marketed for the treatment of psoriasis and osteoporosis.
However, at least some VDR modulators, especially at higher doses, can cause hypercalcemia, which has been linked to vascular calcification, myocardial infarction, heart failure, cardiomyopathy, and stroke. As a result of such side effects and related adverse events, the use of VDR modulators for the treatment of, for example, cardiovascular disease and psoriasis may be limited for safety reasons.
Given the potential limitation of compounds that do result in hypercalcemia it would be advantageous to develop vitamin D receptor modulators that have beneficial therapeutic effects, while having limited effect on increasing serum calcium levels, essentially increasing the therapeutic window for such drugs, and expanding use of VDR modulator therapy.